Adenosine-5′-O-(2-thiodiphosphate) (ADPPS), a P2y purinergic agonist, has been shown to be a potent insulin secretagogue on the isolated rat pancreas. In the present work the effects of ADPpS on insulin, somatostatin, and glucagon secretions were investigated in dogs. In vivo, in anesthetized fasted dogs, i.v. ADPpS (0.1 mg kg−1) induced an immediate increase in insulin and somatostatin-like immunoreactivity (SLI) but not in glucagon pancreaticoduodenal outputs. In conscious fasted dogs, i.v. ADPβS (0.1 mg kg−1) produced an immediate and transient augmentation in plasma insulin levels but not in plasma SLI and glucagon levels. In vitro, the effects of ADPβS were investigated on the isolated uncinate process of dog pancreas, from normal and al-loxan-diabetic animals. In normal uncinate process, in presence of 8.3 mM glucose, ADPβS (1 FM) stimulated insulin and SLI releases but not glucagon release. On uncinate process from diabetic animals, ADPβS (1 μM) retained its stimulating effects but the responses were impaired as compared with normal dogs: Insulin response was drastically diminished and SLI response strongly enhanced. In conclusion, ADPβS is a potent insulin secretory agent in dog. This P2y, purinoceptor agonist, which exerts a direct stimulatory effect on pancreatic SLI, is interestingly devoid of direct glucagonotropic properties.